Broad neutralization of pandemic threat coronaviruses

广泛消除大流行威胁冠状病毒

基本信息

批准号：
10327989
负责人：
Paul D. Bieniasz
金额：
$ 642.33万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-03 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327989
关键词：
2019-nCoV Animal Model Animals Antibodies Antibody Response Antigens B-Lymphocytes Biological Assay COVID-19 COVID-19 pandemic COVID-19 vaccine Cessation of life Cloning Collaborations Complex Coronavirus Coronavirus Infections Coronavirus spike protein Data Effectiveness Ensure Epidemic Epitope Mapping Epitopes Event Evolution Generations Goals Hamsters Health Human Immune response Immunity Immunize Individual Infection Lead Modeling Molecular Monoclonal Antibodies Mus Nature Patients Plasma Population Probability Readiness Reagent Recurrence Reporting Research SARS-CoV-2 infection SARS-CoV-2 spike protein SARS-CoV-2 variant Serology Speed Structure T cell response Techniques Testing Time Vaccination Vaccines Viral Virus Zoonoses animal coronavirus base cohort combat design experience experimental study human disease human monoclonal antibodies improved mutant neutralizing antibody next generation nonhuman primate novel novel coronavirus pandemic coronavirus pandemic disease prevent programs recruit response synergism therapy development vaccine development volunteer weapons zoonotic coronavirus

项目摘要

ABSTRACT-OVERALL The recurrent emergence of coronaviruses from animal reservoirs, and the resulting COVID19 pandemic, necessitates the development of interventions that can target diverse pandemic-threat coronaviruses. Vaccines are among the most powerful means for mitigating viral epidemics but require significant breadth to maximize the probability of effectiveness against unknown viral threats. Currently, first generation vaccines are being deployed to combat SARS-CoV-2, but their effectiveness against emergent SARS-CoV-2 variants and, importantly, against other potential zoonotic coronaviruses is unknown. This program will focus on neutralizing antibodies as a demonstrated and key component of protective immune responses. The Program will improve preparedness against coronaviruses, employing a progressive multistep approach to increase the breadth of vaccine protection. A key component of the research will be to comprehend how neutralizing antibody responses, elicited in humans following natural infection or vaccination, target the SARS-CoV-2 envelope spike and how antibody evolution leads to increased potency and breadth. The identification and characterization of epitopes targeted by SARS-CoV-2 neutralizing antibodies, using multiple approaches, will guide the design of immunogens that aim to elicit neutralizing antibodies targeting as diverse a spectrum of coronaviruses as possible. Several immunogens and delivery strategies will be tested in mice and hamsters that will be challenged with authentic SARS-CoV-2 or a panoply of newly developed challenge models incorporating divergent coronavirus spike proteins. Antibodies elicited in these animals will be analyzed and compared with those found in SARS-CoV-2 immunized humans and immunogens progressively refined and down-selected with the goal of performing vaccine-challenge experiments in nonhuman primates with the most promising candidates. The expertise of each participating team is highly complementary and the program will capitalize and build on the already existing scientific synergy to ensure the efficient and timely completion of the goals.

摘要-总体冠状病毒从动物宿主中反复出现，以及由此引发的新冠肺炎大流行，需要制定针对多种大流行威胁冠状病毒的干预措施。疫苗是减轻病毒流行的最有力手段之一，但需要广泛的努力最大限度地提高对抗未知病毒威胁的有效性的可能性。目前，第一代疫苗被部署来对抗 SARS-CoV-2，但它们对抗新出现的 SARS-CoV-2 变种的有效性，重要的是，针对其他潜在人畜共患冠状病毒的作用尚不清楚。该计划将侧重于中和抗体是保护性免疫反应的已证实的关键组成部分。该计划将得到改善针对冠状病毒的准备，采用渐进的多步骤方法来扩大预防的范围疫苗保护。该研究的一个关键部分是了解中和抗体如何人类在自然感染或接种疫苗后引发的反应以 SARS-CoV-2 包膜为目标尖峰以及抗体进化如何导致效力和广度增加。身份识别和使用多种方法对 SARS-CoV-2 中和抗体靶向的表位进行表征指导免疫原的设计，旨在引发针对不同谱系的中和抗体冠状病毒尽可能。几种免疫原和递送策略将在小鼠和仓鼠中进行测试将受到真正的 SARS-CoV-2 或一系列新开发的挑战模型的挑战整合不同的冠状病毒刺突蛋白。这些动物体内产生的抗体将被分析并与 SARS-CoV-2 免疫人类中发现的相比，免疫原逐渐细化和向下选择的目的是在非人类灵长类动物中进行疫苗挑战实验有前途的候选人。每个参赛团队的专业知识具有很强的互补性，该计划将利用和利用现有的科学协同作用，确保高效、及时地完成目标。